Abstract
Relaxin/insulin-like family peptide receptor 3 (RXFP3) belongs to class A G protein-coupled receptor family. RXFP3 and its endogenous ligand relaxin-3 are mainly expressed in the brain with important roles in the regulation of appetite, energy metabolism, endocrine homeostasis and emotional processing. It is therefore implicated as a potential target for treatment of various central nervous system diseases. Since selective agonists of RXFP3 are restricted to relaxin-3 and its analogs, we conducted a high-throughput screening campaign against 32,021 synthetic and natural product-derived compounds using a cyclic adenosine monophosphate (cAMP) measurement-based method. Only one compound, WNN0109-C011, was identified following primary screening, secondary screening and dose-response studies. Although displayed agonistic effect in cells overexpressing the human RXFP3, it also showed cross-reactivity with the human RXFP4. This hit compound may provide not only a chemical probe to investigate the function of RXFP3/4, but also a novel scaffold for the development of RXFP3/4 agonists.
Highlights
Relaxin/insulin-like family peptide receptor 3 (RXFP3), named as G proteincoupled receptor 135 (GPCR135) or somatostatin- and angiotensin-like peptide receptor (SALPR), is classified as a class A G protein-coupled receptor (GPCR) [1,2,3]
In the HTS campaign with cyclic adenosine monophosphate (cAMP) accumulation assay, the positive signals were evoked by R3/I5, a chimeric peptidic agonist for RXFP3, while the negative signals were assessed in the presence of 1% dimethyl sulfoxide (DMSO)
In the HTS campaign with cAMP accumulation assay, the positive signals were evoked by R3/I5, a chimeric peptidic agonist for RXFP3, while the negative signals3(obfa1c0kground) were assessed in the presence of 1% DMSO
Summary
Relaxin/insulin-like family peptide receptor 3 (RXFP3), named as G proteincoupled receptor 135 (GPCR135) or somatostatin- and angiotensin-like peptide receptor (SALPR), is classified as a class A G protein-coupled receptor (GPCR) [1,2,3] It is predominantly distributed in various regions of the brain, particular in the paraventricular nucleus, with low expression in peripheral tissues [1,4,5]. Relaxin-3, a neuropeptide of the relaxin/insulin-like superfamily with two chains and three disulfide bonds, is the endogenous ligand for RXFP3 [4] It is highly conserved across different species [11] and mainly expressed in mammalian brains [4,6,7,8,9,10,11,12,13,14,15]. RXFP3 stimulation leads to different downstream effects including inhibition of cyclic adenosine monophosphate (cAMP) production [4], elevation in phosphorylation of extracellular regulated protein kinases 1/2 (ERK1/2) [16,17,18], and promotion of β-arrestin recruitment [5,17,18]
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